Neurodegenerative diseases are progressive diseases that cause destructive damage known as nerve cell death. The major neurodegenerative diseases are exemplified by central nerve diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease and the like, and peripheral nerve disorders such as diabetic neuropathy and the like. Most of these diseases are related to aging, and the onset thereof increases with age. However, these diseases also occasionally appear in middle age or even younger ages.
As a result of research related to the structure and function of the brain, the roles of neurotransmitters, neurotrophic factors, and the like are gradually being elucidated, but there is still much that is unknown about the causes of neurodegenerative diseases. Only with Parkinson's disease has the connection between it and a specific neurotransmitter, i.e., dopamine, been clearly shown, and thus a precursor of dopamine, L-Dopa, is used as a drug to relieve the neurological symptoms thereof and recover function. However, L-Dopa does not inhibit the progress of neurodegeneration, and as the condition progresses, i.e., the degeneration/loss of dopamine neurons, the effect of the L-Dopa will be gradually lost. In addition, Alzheimer's disease is a disease in which a large variety of neurons such as acetylcholine neurons, monoamine system neurons, and the like degenerate and/or are lost, and cholinesterase inhibitors are either now on the market or being developed as drugs to treat this disease. However here, like with L-Dopa in Parkinson's disease, these are still in the area of palliative treatment that temporarily improves the neurological symptoms thereof.
Thus, there are no current reports of drugs that protect neurons from the toxicity of factors causing cell death and inhibit the progress of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
In addition, it is said that cell death in neurodegenerative diseases is caused by the toxicity of the factors specific to each respective disease. For example, in Alzheimer's disease, endogenous β-amyloid is considered to be a factor that causes cell death. β-amyloid is a protein composed of between 40 to 43 amino acids, and forms the senile plaque that is a neuropathological hallmark seen in the brains of Alzheimer's disease patients. It has been clearly shown that neuronal cell death is caused when this β-amyloid is added to a primary culture of hippocampus neurons [Science, Vol. 245, pp 417–420 (1989)], and it has been demonstrated that the aggregation of β-amyloid is essential for the manifestation of this toxicity and the like [Neurobiology of Aging, Vol. 13, pp 587–590 (1992) and Journal of Molecular Biology, Vol. 218, pp 149–163 (1991)]. With regard to the mechanism by which the toxicity of β-amyloid is manifested, it is thought that 1) β-amyloid forms ion channels and occurs calcium ions influx, 2) β-amyloid enhances free radicals generation, 3) β-amyloid activates tau-protein kinase I (TPK-I) to promote the phosphorylation of tau, 4) β-amyloid activates microglia, and neurotoxin is secreted from the microglia, and the like.
Recently, it has been clearly shown that neurotrophic factors such as IGF-1 (insulin-like growth factor), NGF (nerve growth factor) and the like inhibit neuronal apoptosis caused by β-amyloid and the like, and that the inhibition of TPK-I/GSK-3β (glycogen synthase kinase-3) caused by the activation of PI-3 kinase played a role in this mechanism [J. Neurosci, Vol. 11, pp 2552–2563 (1991), Science, Vol. 267, pp 2003–2006 (1995), and J. Biol. Chem. Vol. 272, pp 154–161 (1997)]. When TPK-I/GSK-3 β is activated through PI-3 kinase inhibition by β-amyloid and the acetylcholine synthesis reaction system is influenced by the inhibition of pyruvate dehydrogenase (PDH), and thus the content of acetylcholine is also reduced. This concurs with the reduction of the quantity of acetylcholine in brains of Alzheimer's disease patients, and conversely, by activating PI-3 kinase, it is anticipated that nerve cell death will not only be prevented, but that this will cause the quantity of intracerebral acetylcholine to increase, and the neurological symptoms to improve. Furthermore, by inhibiting TPK-I/GSK-3β, an increase in intracerebral glucose utilization that is reduced in Alzheimer's disease can also be expected [J. Biol. Chem Vol. 269, pp 3568–3573 (1994), and Endocrinology, Vol. 125, pp 314–320 (1989)].
In addition, the following compounds have been reported as compounds having a condensed nitrogen-containing heterocyclic group on a benzene ring condensed with a 5-membered heterocyclic, e.g., a furan ring or dihydrofuran ring, or a benzothiophene ring or dihydrobenzothiophene ring.    1) Compounds represented by the following formula and which have bone resorption and bone metabolism inhibitory activity:
(wherein, R1 is hydrogen, lower alkyl, an acyl group, amino, acylamino, nitro, halogen or hydroxy-lower alkyl which may have one or more suitable substituents, R2 is hydrogen, lower alkyl, an acyl group, lower alkoxy, acyl-lower alkyl, aryl, cyano, mono-(or di- or tri-)-halo-lower alkyl. lower alkylthio or hydroxy-lower alkyl which may have one or more suitable substituents, R3 is hydrogen, lower alkyl, lower alkenyl, cyclo-lower alkyl-lower alkyl, halogen, an acyl group, acyl-lower alkyl, acylamino, acylamino-lower alkyl, acyl(lower)alkenyl, acyloxy-lower alkyl, acyl-lower alkylthio-lower alkyl, amino-lower alkyl, mono-(or di-)lower alkylamino, lower alkylthio-lower alkyl, hydroxyimino-lower alkyl which may have one or more suitable substituents, hydroxy-lower alkyl which may have one or more suitable substituents, hydroxy-lower alkylthio-lower alkyl, cyano-lower alkyl, mono-(or di-)lower alkoxy-lower alkyl which may have one or more suitable substituents, lower alkyl substituted with aryl which may have one or more suitable substituents, mono-(or di-)lower alkylamino-lower alkyl, lower alkyl substituted with heterocyclic group which may have one or more suitable substituents, the heterocyclic group which may have one or more suitable substituents, heterocyclicthio, heterocyclicthio-lower alkyl, heterocyclicoxy, heterocyclicoxy-lower alkyl, heterocyclicaminoimino-lower alkyl, aryl, amino or nitro, R2 and R3 may be linked together to form
(1) lower alkylene which may have one or more suitable substituents,
(2) lower alkenylene which may have one or more suitable substituents, or
(3) a group of the formula —(A1)m—W—(A2)n—(wherein A1 and A2 are each lower alkylene which may have one or more suitable substituents or lower alkenylene which may have one or more suitable substituents, W is S—, —S(O)— or N(R5)—(wherein R5 is hydrogen, lower alkyl or an acyl group) and m and n are each integer 0 or 1, X is O or S, Y is vinylene or a group of the formula —NHCO—, —NHSO2—, —OCO—, —OCH2—, —NHCOCO—, —NHCOCH═CH—, —NHCOCH2—, —NHCONH— or N(R6)CO—(wherein R6 is lower alkyl), Z is heterocyclic group which may have one, or more suitable substituents, or aryl which may have one or more suitable substituents, 1 is an integer 0 or 1, and— represents a single bond or a double bond), and pharmaceutically acceptable salts thereof, and more specifically
(WO 95/29907 and JP 9-512795 A).    2) 3,5-dihydroxy heptanoic acids having lipid peroxide formation inhibition activity, represented by the formula:
(wherein R1 is a hydrogen atom, a nitro group, a group represented by —N(R4) R5, wherein R4 and R5 are each an hydrogen atom, lower alkyl group, lower alkenyl group, aryl group, aralkyl group, acyl group, aroyl group, substituted or unsubstituted carbamoyl group, or substituted or unsubstituted thiocarbamoyl group, and R4 and R5 may be combined to form a cyclic amino group. R2 and R3 are each an hydrogen atom or lower alkyl), and 3,5-dihydroxy heptanoic acids represented by the formula:
(wherein, R1 is a hydrogen atom, nitro group, a group represented by —N(R4)R5, and wherein R4 and R5 are each a hydrogen atom, lower alkyl group, lower alkenyl group, aryl group, aralkyl group, acyl group, aroyl group, substituted or unsubstituted carbamoyl group, or substituted or unsubstituted thiocarbamoyl group, and R4 and R5 may be combined together to form a amino group, R2 and R3 are each an hydrogen atom or lower alkyl, R6 is an hydrogen atom, lower alkyl group, alkali metal or alkaline earth metal) (JP 5-194466 A).    3) Compounds used as a herbicide and represented by the formula:
(wherein, R is H, Cl, F, C1–C2 alkyl or C1–C2 alkoxy, R1 is H, F, Cl, Br, CH3, OCH3, CN, CF3, OCF3 or OCF2H,. X1 is O; R2 is H, CH3 or CH2CH3, R3 is H, C1–C4 haloalkyl, CR2R7CN, CN, CR2R4R7, COCl, COR4, C(NOR6) R2, CO2R4, CONR4R2, CHR2OH, CO2 (CH2)2Si (CH3)3, CONR2SO2CH3, CHR2CO2R4, CONHCH(CH3) CONHCH(CH3) CO2CH3, CHR2COR4, CHR2OSO2(C1–C4 alkyl), CHR2OC(O)R4, CHR2OC(O)N(R2)2, CHR2OC(O)N(R2) OCH3, CHR2OC(O)N(R2)Ph, HC═CH2 or C≡CH; R4 is H, C1–C4 alkyl, C1–C4 haloalkyl, C2–C6 alkenyl, C3–C6 alkynyl, C2–C4 halo alkenyl, phenyl, C1–C4 alkylphenyl, C3–C6 alkoxycarbonyl alkyl or (CH2CH2O)bR2; b is 1–6; m is 1; n is 1 or 2; J is
(wherein, X and Y respectively represent O or S). (U.S. Pat. No. 4,881,967).    4) Compounds having antibacterial activity and represented by the formula:
(wherein, m and n are 0 or 1, and the sum of m and n is 1, R is hydrogen or lower alkyl, R′ is R,
or R and R′ together form (CH3)2N—N═,
or form a pyrrole or pyrrolidine, R″ is R, lower alkyl CF3— or ClCH2—, R′″ is a lower alkyl or CF3—), or pharmacologically acceptable salts thereof (U.S. Pat. No. 4,212,865).    5) The compound which is a synthetic intermediate and represented by the formula:
[Tetrahedron Letters, Vol. 37, No. 51, pp 9183–9186, (1996)].
6) The compounds or salts thereof having lipid peroxide formation inhibition activity and represented by the formula:
(wherein, R1 and R2 are the same or different and each is a hydrogen atom, acyl group, alkoxycarbonyl group, aliphatic group, optionally substituted aliphatic group, or an optionally substituted aromatic group, R3, R4 and R5 are the same or different and each is an optionally acylated hydroxy group, an optionally substituted amino group, an optionally substituted alkoxy group, or an optionally substituted aliphatic group, or two of R3, R4 and R5 may form an optionally substituted carbon homocyclic group, R6 and R7 are the same or different and each is an optionally substituted aliphatic group, and moreover at least one of R6 and R7 has methylene at the α-position, R8 and R9 are the same or different and each is a hydrogen atom or an optionally substituted aliphatic group or an optionally substituted aromatic group), or a salt thereof (EP-A-483772 and JP 5-140142 A).    7) The compounds having bone resorption inhibitory activity and represented by the formula:
(wherein, R1 is formyl, carbamoyl-lower alkyl, thiomorpholino carbonyl-lower alkyl, thiomorpholino carbonyl-lower alkyl S-oxide, pyridylamino carbonyl-lower alkyl, pyrazolylamino carbonyl-lower alkyl, triazolylamino carbonyl-lower alkyl, quinolylamino carbonyl-lower alkyl which may have one or more suitable substituents, 3-pyridyl-lower alkyl aminocarbonyl-lower alkyl, 4-pyridyl-lower alkyl aminocarbonyl-lower alkyl, pyridyl ethylamino carbonyl-lower alkyl, pyridyl-lower alkylaminocarbonyl-lower alkyl N-oxide, benzimidazolyl-lower alkylaminocarbonyl-lower alkyl, N-pyridyl-lower alkyl-N-acyl-lower alkylaminocarbonyl-lower alkyl, N-pyridyl-lower alkyl-N-lower alkylaminocarbonyl-lower alkyl, -lower alkylaminocarbonyl-lower alkyl, di-lower alkylaminocarbonyl methyl, quinolyl, 2-hydroxyethyl-2-hydroxy-2-methylpropyl, cyano-lower alkyl, di-lower alkylamino-lower alkyl, pyridyl-lower alkyl, triazolyl-lower alkyl, pyrazolyl-lower alkyl which may have one or more suitable substituents, pyrimidinyl-lower alkyl which may have one or more suitable substituents, dihydrophthalidinyl-lower alkyl which may have one or more suitable substituents, oxadiazolyl-lower alkyl which may have one or more suitable substituents, heterocyclic lower alkenyl which may have one or more suitable substituents, (lower alkoxy)-lower alkylamino-lower alkyl which may have one or more suitable substituents, aryl-lower alkylaminocarbonyl-lower alkyl which may have one or more suitable substituents, arylamino carbonyl-lower alkyl which may have one or more suitable substituents, arylthio-lower alkyl which may have one or more suitable substituents, lower alkyl, or imidazolyl-lower alkyl,    R2 is lower alkyl, protected carboxy or cyano, R3 is halogen or lower alkyl, R4 is hydrogen, nitro or amino, and R5 is halogen, lower alkyl or nitro. However, when 1) R1 is methyl, R2 is protected carboxy or cyano, and 2) when R1 is imidazolylmethyl, R2 is protected carboxy or cyano), or salts thereof (JP 9-124633 A).    8) Compounds having sodium channel modulation activity and which are represented by following formula:
(wherein, R1 and R2 are each a hydrogen atom, a lower alkyl which may be substituted, or acyl,    R3, R4 and R5 are each a lower alkyl which may be substituted or a lower alkoxy with may be substituted, or R4 and R5 may link together to form a 5- or 6-membered carbon homocyclic group,    R6 is lower alkyl,    Ar is an aromatic group which may be substituted, ring A is a 5- to 8-membered nitrogen-containing heterocyclic ring C which may be substituted,    X is a lower alkylene which may be substituted,    Y is a carbon atom or a nitrogen atom,    Za is group represented by the formula CH2, COCH(R7), OCH(R7), SCH(R7) or N(R10)CH(R7)(wherein, R7 is a hydrogen atom or aromatic group which may be substituted, and R10 is a hydrogen atom, hydrocarbon group which may be substituted, or acyl),    Zb is a divalent aliphatic hydrocarbon group which may have a binding bond or a substitutent and may be bonded via an oxygen atom, nitrogen atom or sulfur atom, and m is an integer of 1–3), or salts thereof (WO98/08842).
It is thought that compounds which exhibit excellent brain permeability and which have neurotrophic factor-like activity, neurotrophic factor reactivity-enhancing activity, and activity that promotes neuropoiesis and neuroregeneration enhancing after neurodegeneration, will inhibit nerve cell death in neurodegenerative diseases such as Alzheimer's disease and the like, and can improve the symptoms of the same. Accordingly, it is desirable to develop compounds having neurotrophic factor-like activity and neurotrophic factor reactivity-enhancing activity, and further have excellent pharmacological activities such as activity which inhibits the cytotoxicity of β-amyloid and the like in order to protect neurons, or activity which protects neurons from toxicity factors which cause cell death, and thus are useful as a pharmaceutical for preventing/treating neurodegenerative diseases and the like.
The present applicant took this situation into consideration, and first, successfully synthesized compounds or the salts thereof represented by the formula:
wherein (i) a group is represented by the formula:
(in the formula, ring A represents a benzene ring which may be substituted, and ring B represents a 5- to 7-membered nitrogen-containing heterocyclic group which may be substituted with a halogen or an optionally substituted hydrocarbon group) or    (ii) a group is represented by the formula:
(in the formula, R4 represents (1) a aliphatic hydrocarbon group which may be substituted with an aromatic group that may be substituted, and wherein the aliphatic hydrocarbon group may have further substituents or (2) an acyl group that includes an aromatic group that may be substituted, R5 represents hydrogen, C1-6 alkyl or an acyl group),    when W is Wa, R3 represents a hydrogen atom, a hydrocarbon group that may be substituted, or a heterocyclic group that may be substituted, ring C represents a benzene ring which, other than the group represented by Wa, may also have a substituent selected from a halogen, a lower alkyl that may be halogenated, lower alkoxy that may be halogenated, and a lower alkylthio which may be halogenated,    when W is Wb, R3 represents a C6-14 aryl group that may be substituted, and ring C represents a benzene ring which may also have further substituents in addition to the group represented by Wb. However, when— represents a double bond, the partial structure
the applicant then discovered that the compounds have pharmaceutical activities such as neurotrophic factor-like activity, neurotrophic factor reactivity-enhancing activity, inhibiting activity of β-amyloid cytotoxicity, and the like, and moreover, discovered that these compounds had extremely low toxicity, excellent brain penetrability properties, and thus could be sufficiently satisfactory as a pharmaceutical having neurodegeneration inhibitory activity, and filed a patent application (WO00/34262).